Merck’s Investigational NNRTI, Doravirine, Meets Primary Efficacy Endpoint of Non-Inferiority to Efavirenz, Both in Combination with Other Antiretroviral Agents, in Pivotal Phase 3 Trial for Treatment of HIV-1 Infection

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July 25, 2017 7:35 am ET

Merck Plans to Submit New Drug Applications with the U.S. FDA in Q4 2017

Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced the presentation of results from the DRIVE-AHEAD study,
the second of two pivotal Phase 3 clinical trials evaluating the
efficacy and safety of doravirine, the company’s investigational,
non-nucleoside reverse transcriptase inhibitor (NNRTI), for the
treatment of HIV-1 infection. At 48 weeks, the study showed that a
once-daily single tablet, fixed-dose combination of doravirine (DOR),
lamivudine (3TC), and tenofovir disoproxil fumarate (TDF) met its
primary efficacy endpoint of non-inferiority based on the proportion of
participants achieving levels of HIV-1 RNA less than 50 copies/mL at 48
weeks of treatment, compared to a fixed-dose combination of efavirenz
(EFV), emtricitabine (FTC), and TDF, in treatment-naïve adults infected
with HIV-1.

In addition, through 48 weeks, statistically significantly fewer
patients taking DOR/3TC/TDF reported pre-specified categories of
neuropsychiatric events (dizziness, sleep disorders and disturbances,
and inability to think clearly or concentrate) than patients receiving
the EFV/FTC/TDF regimen. Treatment with DOR/3TC/TDF also showed a
statistically significant lower change from baseline in fasting low
density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein
cholesterol (non-HDL-C) compared to EFV/FTC/TDF at Week 48. Findings
from the ongoing DRIVE-AHEAD Phase 3 trial were featured as part of a
late-breaking oral presentation session at the 9th International
Conference on HIV Science (IAS
2017
) taking place in Paris, France, from July 23-26, 2017.

“Data from DRIVE-AHEAD at 48 weeks show that a fixed-dose combination
tablet containing doravirine achieved viral suppression in HIV-1
infected treatment-naïve adults, comparable to a fixed-dose combination
containing efavirenz,” said Dr. Kathleen Squires, professor and director
of infectious diseases, Thomas Jefferson University, Philadelphia, PA, a
study investigator. “The results for doravirine are encouraging, as it
may offer appropriate patients a new single-tablet treatment option.”

After 48 weeks of treatment, 84 percent of the 364 treatment-naïve
patients taking once-daily DOR/3TC/TDF achieved levels of HIV-1 RNA <50
copies/mL compared to 81 percent of the 364 patients taking once-daily
EFV/FTC/TDF, with an estimated treatment difference of 3.5 percent (95
percent confidence interval; -2.0, 9.0). Increases in mean CD4+ T-cell
counts from baseline for the DOR/3TC/TDF and EFV/FTC/TDF groups were 198
and 188 cells/mm3, respectively, with an estimated treatment
difference of 10.1 (95 percent confidence interval; -16.1, 36.3). In
addition, comparable efficacy was observed across both treatment groups
among individuals with high viral load (HIV-1 RNA >100,000 copies/mL) at
baseline, which consisted of 69 patients in the DOR/3TC/TDF group and 73
patients in the EFV/FTC/TDF group (Observed Failure approach). Of those
patients with a high viral load (HIV-1 RNA >100,000 copies/mL) at
baseline, 81 percent in the DOR/3TC/TDF group and 81 percent in the
EFV/FTC/TDF group achieved the study’s primary endpoint of <50 copies/mL
of HIV-1 RNA, with a treatment difference of 1.0 percent (95 percent
confidence interval; -12.4, 14.3).

The study also met its primary safety endpoint, showing that treatment
with DOR/3TC/TDF resulted in fewer patients reporting events of several
pre-specified neuropsychiatric adverse events compared to EFV/FTC/TDF by
Week 48, including dizziness (8.8 percent versus 37.1 percent); sleep
disorders and disturbances (12.1 percent versus 25.5 percent); and
inability to think clearly or concentrate (4.4 percent versus 8.2
percent). The 2-sided p-values for treatment differences with respect to
these three pre-specified categories were p<0.001, p<0.001, and p=0.033,
respectively.

Furthermore, the reported rates of drug-related adverse events were
lower in the group taking DOR/3TC/TDF (31 percent; 113/364) versus the
group taking EFV/FTC/TDF (63 percent; 229/364), representing a -31.9
percent treatment difference (95 percent confidence

interval, -38.6, -24.8). Treatment discontinuations due to adverse
events for DOR/3TC/TDF and EFV/FTC/TDF were 3 percent (11/364) and 7
percent (24/364), respectively.

The most commonly reported adverse events occurring in ≥10 percent of
patients in the DOR/3TC/TDF group compared to the EFV/FTC/TDF group
were: headache (13 percent vs. 12 percent); diarrhea (11 percent vs. 14
percent); nasopharyngitis (11 percent vs. 9 percent); dizziness (9
percent vs. 37 percent); nausea (8 percent vs. 11 percent); abnormal
dreams (5 percent vs. 12 percent) and, rash (5 percent vs. 12 percent),
respectively.

Treatment-emergent viral mutations leading to any drug-associated
resistance was detected in 1.6 percent of patients in the group
receiving DOR/3TC/TDF, and 3.3 percent of those in the EFV/FTC/TDF
group, respectively, through Week 48.

An analysis of fasting lipid levels showed a statistically significant
treatment difference in mean changes from baseline in fasting LDL-C and
non-HDL-C between the two treatment groups (p<0.0001 for both
cholesterol types). The mean changes from baseline in levels of fasting
LDL-C and non-HDL-C among the group taking DOR/3TC/TDF was -1.6 mg/dL
and -3.8 mg/dL, respectively; compared to the group taking EFV/FTC/TDF
which was +8.7 mg/dL and +13.3 mg/dL, respectively.

“For more than 30 years, Merck has been at the forefront of HIV research
and the development of new treatments that make a difference for people
living with HIV,” said Dr. George Hanna, associate vice president,
clinical research, Merck Research Laboratories. “The development
of doravirine is the result of a decade of Merck research.
Based on our encouraging Phase 3 study findings, we plan to file
regulatory applications in Q4 2017.”

About DRIVE-AHEAD

DRIVE-AHEAD is an ongoing Phase 3 multicenter, double-blind, randomized,
active comparator-controlled clinical trial evaluating the safety and
efficacy of a once-daily, single-tablet, fixed-dose combination
containing doravirine 100 mg, lamivudine 300 mg and tenofovir disoproxil
fumarate 300 mg versus a once-daily, single-tablet, fixed-dose
combination containing efavirenz 600 mg, emtricitabine 200 mg, and
tenofovir disoproxil fumarate 300 mg in treatment-naïve HIV-1 infected
adults. The primary endpoint of the clinical trial was the proportion of
participants with levels of HIV-1 RNA <50 copies/mL at Week 48. The
primary safety endpoint was the proportion of participants with
neuropsychiatric adverse events through Week 48 in the following
pre-specified categories: dizziness, sleep disorders and disturbances,
and the inability to think clearly or concentrate. The trial consists of
a 96-week double-blind treatment period (base study) and an open label
extension after participants complete the base study.

For further information regarding DRIVE-AHEAD please visit www.clinicaltrials.gov
clinical trial registry number NCT02403674.

About Doravirine

Doravirine (MK1439) is an investigational NNRTI being evaluated by Merck
for the treatment of HIV-1 infection. Doravirine is being evaluated in
several ongoing clinical trials as a once-daily fixed dose combination
with 3TC and TDF or individually for use in combination with other
antiretroviral agents. Phase 3 trials include DRIVE-AHEAD, a trial
comparing DOR/3TC/TDF to EFV/FTC/TDF in treatment-naïve adults;
DRIVE-FORWARD, a trial comparing DOR to once-daily ritonavir-boosted
darunavir (DRV+r), each administered in combination with FTC/TDF or
abacavir (ABC)/3TC, in treatment-naïve adults; and DRIVE-SHIFT, a trial
evaluating a switch to DOR/3TC/TDF in HIV-1 infected adults who are
currently virologically suppressed on another antiretroviral regimen.
Other ongoing Phase 2 clinical trials include an evaluation of
DOR/3TC/TDF in treatment-naïve adults with transmitted resistance to
NNRTIs and in individuals switching from efavirenz due to intolerability.

About Merck

For more than a century, Merck, a leading global biopharmaceutical
company known as MSD outside of the United States and Canada, has been
inventing for life, bringing forward medicines and vaccines for many of
the world’s most challenging diseases. Through our prescription
medicines, vaccines, biologic therapies and animal health products, we
work with customers and operate in more than 140 countries to deliver
innovative health solutions. We also demonstrate our commitment to
increasing access to health care through far-reaching policies, programs
and partnerships. Today, Merck continues to be at the forefront of
research to advance the prevention and treatment of diseases that
threaten people and communities around the world – including cancer,
cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease
and infectious diseases including HIV and Ebola. For more information,
visit www.merck.com
and connect with us on TwitterFacebookInstagram,
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and LinkedIn.

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Merck
Media:
Doris Li, 908-246-5701
Carmen de Gourville, 267-664-0146
Investor:
Teri Loxam, 908-740-1986
Amy Klug, 908-740-1898

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